EA002469B1 - Method for treating fungal infections - Google Patents

Abstract

1. A method of treating fungal infection which comprises administering therapeutically effective amounts of a pneumocandin derivative of the formula (1): or a pharmaceutical acceptable salt thereof and polyene, said polyene is amphotericin B. 2. A method of treating fungal infection which comprises administering therapeutically effective amounts of a pneumocandin derivative of the formula (1): or a pharmaceutical acceptable salt thereof and azole, said azole is fluconazole. 2. The method of Claim 1, wherein the infection is caused by a fungal pathogen selected from Cryptococcus spp., Candida spp., or Aspergillus spp. 3. The method of Claim 2, wherein the infection is caused by a fungal pathogen selected from Cryptococcus spp., Candida spp., or Aspergillus spp.

Description

This invention relates to antifungal combination therapy, including the use of known antifungal agents, such as azoles or polyenes, in combination with an antifungal agent derived from pneumocandin. More specifically, the invention relates to antifungal combination therapy, including the use of azoles such as fluconazole (hereinafter referred to as ΕΟΖ) or polyenes such as amphotericin B (hereinafter referred to as AtB) in combination with a pneumocandin derivative of the structure

or its pharmaceutically acceptable salt or its other pharmaceutically acceptable formulations.

It has been shown that this combination therapy is useful against conditionally pathogenic microorganisms such as Sulfur sossis spr., Sapysha spr., AzregdShiz spr.

BACKGROUND OF THE INVENTION

Currently, there is an increasing need for drugs that are effective in combating opportunistic mycotic infections, such as Sulfurosossis sp. Spare Sp. ., Oesha and Iseoise fungi and Speechisus from sagsha. Currently used drugs, i.e. polyenes, such as amphotericin B, cause serious side effects, and azoles, such as fluconazoles, have only fungistatic effects. Pneumocandins, which belong to echinocandins, are cyclic hexapeptides that inhibit the synthesis of β, ββ-Ό-glucan of the cell membrane. Pneumocandins have been shown to be effective under the conditions of sh1yuo in relation to Sapysha spr., Ppeisosus iz sagshi, Azregd Shiz spr., As well as in relation to other fungal pathogens listed above. However, the pneumocandins themselves have little activity against SgurJusossis spr.

Combination therapy with antifungal drugs may provide additional treatment options for SgurYusossiz and other fungal pathogens.

Previous studies have led to an increase in the effectiveness of other pneumocandin derivatives with respect to Crurium Yossossis peoGogshapz in combination with amphotericin B and fluconazole (Algin // o e! A1. Apisyugo. Aderoz Syesho. 1995, 39: 1077-1081 and VagI / a1 e! A1. , ApByugo. Adep! S Siesho. 1995, 39: 1070-1076). However, none of these studies reported the results found when using compound I as a pneumocandin derivative.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to antifungal combination therapy, including the use of known antifungal agents, such as azoles or polyenes, in combination with an antifungal agent derived from pneumocandin. More specifically, the invention relates to antifungal combination therapy comprising the use of azoles, such as fluconazole or polyenes, such as amphotericin B in combination with a compound of structure

or its pharmaceutically acceptable salt or its other pharmaceutically acceptable formulations.

In particular, combination therapy, as has been shown, is useful in the fight against opportunistic microorganisms such as Sgur1ossiz spr., SapyMa spr., AzregdShiz spr.

Compound I is described in US patent No. 5378804. Its preparation is described in this patent, as well as in US patent No. 5552521.

It is contemplated that other pneumocandin derivatives, such as those described in US Pat. No. 6,516,756 and in co-pending applications 07/936558, 07/936561, 08/058657, 08/055996, 08/378687 and 60/006505, would be useful in combination therapy. Azole, polyene and other antifungal agents can be administered orally or parenterally. Compound I is preferably administered parenterally, but the administration is not limited to this method, and it can also be administered by other methods, such as oral, intramuscular or subcutaneous.

As shown below, combination therapy leads to increased effects when using subinhibitory concentrations of all components. These effects can be shown in the experiments of ίη νίίτο and ίη νΐνο using the clinical and natural lines of S. peoGogtap5. C. a1b1sap§ and A. gitscha1i8.

The invention is further described in connection with the following, non-limiting examples.

Examples

Experiments show that the combination therapy of compound I with AtV and ΕΟΖ to control C. peoHogtap leads to an increase in activity against S. peoHogtash lines under conditions of ίη tight. Experiments show that the combination therapy of compound I with AtB in relation to C. a1b1cap8 and A. £ it1da! U8 leads to an increase in activity under conditions of antigens. This is shown using the broth microdilution method, which is the standard method for evaluating antifungal sensitivity proposed by SCL8 (protocol M27-T). Subinhibitory concentrations of compound I are used in combination with subinhibitory concentrations of AtB. Minimum inhibitory concentrations (M1C) for AtB and compound I are defined as the lowest drug concentration at which there is no growth. MK. ' for BSΖ is defined as the lowest concentration, which leads to visual turbidity less than or equal to 80% inhibition compared to inhibition obtained by control without an antifungal agent.

The results of the determination of antifungal sensitivity show that colony forming units (CFU) are significantly reduced when amphotericin B in certain concentrations (0.0075, 0.015 and 0.03 μg / ml) is combined with compound I in certain concentrations (4, 8 and 16 μg / ml). In addition, the administration of compound I significantly increases the activity of fluconazole by reducing the amount at certain concentrations (0.25, 0.50 and 1.0 μg / ml).

An additional drug combination test under ίη tygo conditions is conducted to evaluate the effect of combinations of compound I with AtV and Ρί'Ζ in relation to clinical isolates. The apparent antagonism between compound I and AtB in relation to the lines C. colibus8. A. Yeitschai. 15 and C. neoGot ^ -n not observed. Fractional indices of inhibition (Ghashyoshyllonomyosyllosis - NS) are approximately 0.50 or less, which indicates additional or synergistic activity. The results suggest that compound I can increase the activity of BSΖ and AtB, and show the potential role of compound I in combinations relative to fungi that are less sensitive or insensitive to compound I when it is used separately.

Studies of the interaction and effectiveness of drugs - compounds I with AtV or with BSΖ are carried out in relation to disseminated candidiasis, aspergillosis and cryptococcosis. The results show that there are no side effects of the mixtures at high, normal, and lower concentrations, and there is no antagonism of the efficacy of AtB or BS с in combination with compound I. It turns out that, in relation to C. lycis, combinations of compound I are more effective in doses of 0.03 mg / kg and lower AtV in doses of 0.03 mg / kg and lower compared with the use of a single agent. Similar results are obtained when using BSΖ in doses of 0.31 mg / kg and lower in combination with 0.03 mg / kg of compound I. Significant improvements in effectiveness (from 10 to> 800-fold in ΕΌ values) are noted when using combinations of compound I, used in doses in the range from 0.03 to 2 mg / kg, with AtV used in doses in the range from 0.03 to 0.5 mg / kg in relation to A. Git1§a1i8. A significant improvement in survival was noted when using compound I at a dose of 0.008 mg / kg in combination with AtV at a dose of 0.12 mg / kg compared with compounds administered separately.

As was discovered as a result of studies of drug combinations under ίη ugo conditions carried out with compound I and AtB, the HC values are approximately 0.50, which indicates additional or synergistic activity under ίη у | уо conditions. In addition, a study of mouse cryptococcosis activity shows a lack of BSΖ antagonism in combination with compound I. A beneficial effect on efficacy is observed in relation to C. neoGoth ^ -b when using combinations of compound I with BSΖ in certain concentrations.

The above description implies that changes may be made by a person skilled in the art. For example, it is understood that combination therapy using azoles other than fluconazole and pneumocandin derivatives other than compound I may be effective against fungal infections caused by said fungal pathogens. Accordingly, it is understood that these examples should be considered as illustrative, and that the described invention should be limited only by the following claims.

Claims (4)

1. A method of treating a fungal infection, comprising administering therapeutically effective amounts of a pneumocandin derivative of formula (I) or a pharmaceutically acceptable salt and polyene thereof, wherein the polyene is amphotericin B. 2. A method of treating a fungal infection, comprising administering therapeutically effective amounts of a pneumocandin derivative of formula (I) or a pharmaceutically acceptable salt and azole thereof, wherein the azole is fluconazole. 3. The method according to claim 1, characterized in that the infection is caused by a fungal pathogen selected from Cgur1ossoss spr., Sai616a spr. or LzregdShiz spr. 4. The method according to claim 2, characterized in that the infection is caused by a fungal pathogen selected from Cgur1ossoss spr., SaibMa spr. or LzregdShiz spr.